Regorafenib shown to augment antitumor effect of anti-PD-1 immunotherapy in advanced gastric cancers

Medical Xpress / Kumamoto University / Cancer Research ^ | Jan. 23, 2023 | Takahiko Akiyama et al

[ConservativeMind]

Fibrotic cancers such as gastric cancers are highly resistant to conventional therapies like immune checkpoint inhibitors. Cancer-associated fibroblasts (CAFs) are an important part of this resistance. Now, researchers have demonstrated that regorafenib and anti-PD-1 work synergistically to target CAFs, in turn modifying the cancer stroma and reducing fibrotic tumor growth.

Gastric cancer (GC) is the third leading cause of death worldwide.

Diffuse-types GCs (DGCs) are characterized by rapid progression.

An important component of fibrotic cancer stroma is cancer-associated fibroblasts (CAFs), which are responsible for rapid GC progression and resistance to standard therapies. The interaction between platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) amplifies the growth of fibroblasts in GC.

The team found that high levels of PDGF C and D ligands led to poor prognosis of GC. Further investigations revealed that PDGF-PDGFβ interaction in DGC stroma also contributed to poor prognosis.

In vitro as well as fibrotic mouse model studies demonstrated that CAFs stimulated by PDGFs produced specific chemokines that recruit immunosuppressive cells into tumors. As a result, tumors could easily evade the immune system and become resistant to immune checkpoint inhibitors. CAF growth was significantly inhibited by anti-PDGFR antibodies, further validating the role of PDGFRα/β in tumor fibrosis and progression.

Additionally, transcriptomics and RNA sequencing analyses of CAFs revealed that regorafenib strongly blocked the expression of chemokines involved in leucocyte migration into the cancer environment, both in vitro and in vivo.

This finding underscores the potential of regorafenib in reversing CAF-associated immune suppression by remodeling the fibrotic stroma. Based on findings, the team evaluated the impact of combining regorafenib and immune check point inhibitors (e.g., anti-PD-1), in treating GCs in mouse models. Regorafenib enhanced the anti-tumor activity of anti-PD-1 in fibrotic tumors. This synergistic effect of two treatment modalities is a breakthrough in the therapeutic management of GCs.

[ConservativeMind]

Regorafenib is currently available and used for other cancers.

[ConservativeMind]

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